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Expanding the Genetic Heterogeneity of Intellectual Disability Shams Expanding the genetic heterogeneity of intellectual disability Shams Anazi*1, Sateesh Maddirevula*1, Yasmine T Asi2, Saud Alsahli1, Amal Alhashem3, Hanan E. Shamseldin1, Fatema AlZahrani1, Nisha Patel1, Niema Ibrahim1, Firdous M. Abdulwahab1, Mais Hashem1, Nadia Alhashmi4, Fathiya Al Murshedi4, Ahmad Alshaer12, Ahmed Rumayyan5,6, Saeed Al Tala7, Wesam Kurdi9, Abdulaziz Alsaman17, Ali Alasmari17, Mohammed M Saleh17, Hisham Alkuraya10, Mustafa A Salih11, Hesham Aldhalaan12, Tawfeg Ben-Omran13, Fatima Al Musafri13, Rehab Ali13, Jehan Suleiman14, Brahim Tabarki3, Ayman W El-Hattab15, Caleb Bupp18, Majid Alfadhel19, Nada Al-Tassan1,16, Dorota Monies1,16, Stefan Arold20, Mohamed Abouelhoda1,16, Tammaryn Lashley2, Eissa Faqeih17, Fowzan S Alkuraya1,3,16,21,18 *These authors have contributed equally 1Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 2Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK. 3Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. 4Department of Genetics, College of Medicine, Sultan Qaboos University, Sultanate of Oman. 5King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia. 6Neurology Division, Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia. 7Armed Forces Hospital Khamis Mushayt, Department of Pediatrics and Genetic Unit, Riyadh, Saudi Arabia. 9Department of Obstetrics and Gynecology, King Faisal Specialist Hospital, Riyadh, Saudi Arabia 10Department of Ophthalmology, Specialized Medical Center Hospital, Riyadh, Saudi Arabia. 11Division of Pediatric Neurology, Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia. 12Pediatric Neurology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. 13Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Qatar. 14Department of Pediatrics, Division of Neurology, Tawam Hospital, Al Ain, United Arab Emirates. 15Division of Clinical Genetics and Metabolic Disorders, Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates. 16Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. 17Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia. 18Spectrum Health Genetics, Grand Rapids, MI, USA 19King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Genetics Division, Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia 20King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal, 23955-6900, Saudi Arabia 21Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia Authors declare no conflict of interest Corresponding author: [email protected] ABSTRACT Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 67 families (104 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD as a particularly compelling candidate in which we identified biallelic likely deleterious variants in two ID families. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms. INTRODUCTION Intellectual disability (ID) is a common morbidity that affects 1-3% of the population 1; 2. The resulting functional impairment varies depending on the severity of ID, which ranges from mild to severe as quantified by the intelligence quotient (IQ) score. The etiology of ID is highly heterogeneous although genetic forms are increasingly recognized as a major etiological category. De novo genetic and genomic variants account for at least 50% of severe ID in outbred populations 3. In contrast, the majority of ID in highly inbred populations is caused by recessive mutations 4; 5. The recent expansion in the use of genomic sequencing techniques (primarily whole-exome sequencing) has resulted in a rapid expansion of the genetic determinants of ID. In the case of dominant causes, very large sequencing projects have concluded that the nearly all major ID genes have likely been identified 6. This appears to be in striking contrast to recessive ID where recent large sequencing projects have revealed very little overlap in their lists of novel candidate genes, which suggests that a significant proportion of recessive ID genes have yet to be identified 4; 7-9. Consanguinity loops are not only helpful in facilitating the discovery of novel recessive disease genes, including ID genes, but they also facilitate the occurrence of homozygous truncating (knockout) alleles in genes previously reported as candidates, which strongly corroborates those tentative disease-gene links 10. Additionally, consanguinity can unmask recessive mutations in genes that are only known to cause diseases in an autosomal dominant fashion 11. This can lead to a remarkably different phenotype from the previously reported dominant one 5; 12-14. Finally, certain classes of pathogenic mutations may evade detection/interpretation by the typical genomic sequencing and only come to focus with the help of positional mapping aided by consanguinity 15. In this study, we attempted to exploit the above advantages of consanguinity to expand the morbid genome of ID. MATERIALS AND METHODS Human Subjects All patients with documented ID or significant component of cognitive impairment in the setting of developmental delay in a young child were eligible. Only patients in whom we identified variants that potentially explain their phenotype were included. Those with potentially causal variants that are not novel were excluded. Available family members were recruited for segregation analysis as appropriate. A written informed consent was obtained from all subjects prior to participation in accordance with a KFSHRC IRB-approved research protocol (RAC# 2121053). Mutation Identification All subjects with negative family history had molecular karyotyping performed as described before4; 16. Only those in whom normal results were obtained were included in subsequent analysis. Specifically, a previously described multigene panel (599 genes) were used to screen for mutations in known ID genes 17. If negative, we proceeded with autozygome analysis and whole exome sequencing (WES) as described before 17. Some patients were directly tested by clinical WES. Variant classification was according to the recent ACMG guidelines 18. For PM2 score, we used gnomAD as well as an in-house ethnically matched database of 2,363 exomes and 1,607 neuro gene panels. We only included cases in whom pathogenic or likely pathogenic variants were identified. The only exceptions are those in whom variants in candidate genes were identified. These were included for the purpose of proposing novel candidate genes. Candidacy of these novel genes was based on several factors as described before 4; 16. Sanger confirmation was performed for all reported variants and segregation with the phenotype was confirmed whenever samples from relatives were available. RTPCR and Molecular Cloning RNA isolation and gene-specific RTPCR were as described 19. PCR amplified product was subjected to molecular cloning into sequencing vector pGEM-T Easy (Promega) followed by sequencing with SP6/T7 polymerase primers. Tissue Collection Samples were collected from brains donated to the Queen Square Brain Bank for Neurological Disorders, Institute of Neurology, University College London, UK. The donations were made according to ethically approved protocols, and tissue at Queen Square Brain Bank is stored under a license issued by the Human Tissue Authority (No. 12198). Computational structural analysis of mutants Sequences were retrieved from the Uniprot database. SwissModel and RaptorX 20; 21 were used to produce homology models. RaptorX was used for prediction of secondary structure and protein disorder. QUARK 22 was used for ab initio structural modeling. Models were manually inspected, and mutations evaluated, using the Pymol program (pymol.org). Immunohistochemistry Immunohistochemistry Formalin-fixed paraffin-embedded tissue blocks from the frontal cortex, hippocampus and cerebellum of normal
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